Design, synthesis, and evaluation of analogues of 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide as orally available general anesthetics

Article abstract of DOI:10.1021/jm020546r

We have recently discovered a novel class of compounds that have oral general anesthetic activity, potent anticonvulsant activity, and minimal hemodynamic effects. The 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide (1) demonstrated potent ability to reduce the minimum alveolar concentration (MAC) of isoflurane, with no effects on heart rate or blood pressure at therapeutic concentrations. Analogue 1 also had potent oral anticonvulsant activity against maximal electroshock (MES) and subcutaneous metrazol (scMET) models with a therapeutic index of 10 for MES activity. In this study, we further synthesized nine new racemic analogues and evaluated these compounds for effects on isoflurane MAC reduction and blood pressure. Preliminary data demonstrate potent reduction in the isoflurane MAC for two new compounds. Current mechanistic studies were unrevealing for effects on voltage-gated ion channels as a putative mechanism. Liposomal partitioning studies using ¹⁹F NMR reveal that the aromatic region partitions into the core of the lipid. This partitioning correlated with general anesthetic activity of this class of compounds. Further, compound 1 was used at a concentration of 1 mM and slightly enhanced GABA_A current in hippocampal neurons at 10 μM. Altogether, 3,3,3-trifluoro-2-hydroxy-2-phenyl-propionamide exhibited excellent oral general anesthetic activity and appears devoid of significant side effects (i.e., alterations in blood pressure or heart rate).

Full text of DOI:10.1021/jm020546r

2494
J . Med. Chem. 2003, 46, 2494-2501
Design , Syn th esis, a n d Eva lu a tion of An a logu es of
3,3,3-Tr iflu or o-2-Hyd r oxy-2-P h en yl-P r op ion a m id e a s Or a lly Ava ila ble Gen er a l
An esth etics
Indrani Choudhury-Mukherjee,† Hilary A. Schenck,† Sylvia Cechova,§ Thomas N. Pajewski,§ J aideep Kapur,‡
J effrey Ellena,† David S. Cafiso,† and Milton L. Brown*,†,‡
Departments of Chemistry, Anesthesiology, and Neurology, University of Virginia, McCormick Road, P.O. Box 400319,
Charlottesville, Virginia 22904
Received December 4, 2002
We have recently discovered a novel class of compounds that have oral general anesthetic
activity, potent anticonvulsant activity, and minimal hemodynamic effects. The 3,3,3-trifluoro-
2-hydroxy-2-phenyl-propionamide (1) demonstrated potent ability to reduce the minimum
alveolar concentration (MAC) of isoflurane, with no effects on heart rate or blood pressure at
therapeutic concentrations. Analogue 1 also had potent oral anticonvulsant activity against
maximal electroshock (MES) and subcutaneous metrazol (scMET) models with a therapeutic
index of 10 for MES activity. In this study, we further synthesized nine new racemic analogues
and evaluated these compounds for effects on isoflurane MAC reduction and blood pressure.
Preliminary data demonstrate potent reduction in the isoflurane MAC for two new compounds.
Current mechanistic studies were unrevealing for effects on voltage-gated ion channels as a
putative mechanism. Liposomal partitioning studies using 19F NMR reveal that the aromatic
region partitions into the core of the lipid. This partitioning correlated with general anesthetic
activity of this class of compounds. Further, compound 1 was used at a concentration of 1 mM
and slightly enhanced GABAA current in hippocampal neurons at 10 µM. Altogether, 3,3,3-
trifluoro-2-hydroxy-2-phenyl-propionamide exhibited excellent oral general anesthetic activity
and appears devoid of significant side effects (i.e., alterations in blood pressure or heart rate).
In tr od u ction
selectivity,6-8 and saturability at several receptor tar-
gets,includingγ-aminobutyricacid(GABAAandGABAB),9,10
nicotinic,11 and voltage-gated ion channels such as
calcium,12,13 potassium,14 and sodium.15-20 Because of
the increasing studies on the direct effects of inhala-
tional anesthetics on ion channels and receptors, many
researchers now believe these targets are the site(s) of
action of volatile anesthetics.21 However, debate con-
tinues as to whether the anesthetic “receptor” is a
membrane lipid or protein complex.
General anesthesia is defined by reversible uncon-
sciousness, lack of response to noxious stimuli, and
amnesia induced by chemical agents. Successive im-
provements in these agents produced today’s inhaled
anesthetics, compounds that allow precise control over
the anesthetic state. Such control extends to induction,
maintenance of, and recovery from anesthesia.1 Present
mechanism(s) and physiological site(s) of action of
general anesthetics remain controversial and multi-
modal. On the basis of the correlation between oil
solubility and anesthetic potency, Meyer and Overton
originally proposed that anesthetic drugs acted on the
cell’s lipid membranes.2 However, an observation in
1984 by Franks and Lieb3 indicated that anesthetic
inhibition of purified (i.e., lipid-free) firefly protein,
luciferase, closely related to potency. This observation
challenged Meyer and Overton’s theory and introduced
the concept of a protein-binding site. Along with the lack
of stereoselective differences in lipid solubility,4 these
results strongly argue against a simple lipid site as a
primary mechanism of action. More recently, it has been
demonstrated that anesthetic agents act on or within
specific proteins of the cellular membrane of neurons,
or both. Anesthetic compounds have demonstrated
specific structure-activity relationships (SAR),5 stereo-
Currently available general anesthetics are either not
optimal or not without side effects.21 Common post-
anesthetic side effects include somnolence, nausea,
emesis, transient disorders of mentation (emergence
excitement), post-anesthetic tremor (shivering), and
dysrhythmias (particularly sinus tachycardia). Thus,
there is a need for improved anesthetic agents having
decreased post-anesthetic side effects along with in-
creased anesthetic control.
Propofol, a simple formulation of 2,6-diisopropylphe-
nol, is an effective intravenous anesthetic and is used
for induction and maintenance of general anesthesia
(Figure 1). This compound, when administered by
continuous infusion or by intermittent bolus doses, has
found increased use for its quick anesthetic onset and
titratability. Unfortunately, propofol has significant
limitations due to poor aqueous solubility and must be
formulated as an oil-water emulsion. Good sterile
technique must also be observed upon administration
of this preparation since bacterial contamination has
been associated with sepsis and death. Further, propofol
* Address correspondence to this author. Tel.: 434-982-3091. E-
mail: mlb2v@virginia.edu.
† Department of Chemistry.
§ Department of Anesthesiology.
‡ Department of Neurology.
10.1021/jm020546r CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/14/2003

Propionamide Analogues as Oral General Anesthetics
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2495
Sch em e 1a
a
Reaction Conditions: (a) TMSCN, KCN, 18-crown-6; (b): 15% HCl; (c) 1,4-dioxane, concd. HCl, HCl gas; (d) BnBr, Bu4NBr, 5% NaOH,
CH2Cl2; (e): LiAlH4, Et2O; (f) 1,4-dioxane, concd. HCl, 100 °C.
F igu r e 1. Common general anesthetics.
F igu r e 2. Potential themisone metabolism.
administration can lower blood pressure as a result of
a decrease in systemic vascular resistance, cardiac
contractility,22 and preload.
Over the years, we have been involved with the
National Institutes of Health’s Neurological Diseases
and Strokes Anticonvulsant Drug Development Pro-
gram (NINDS ADD program). Recent evaluation in the
NINDS ADD program revealed 3,3,3-trifluoro-2-
hydroxy-2-phenyl-propionamide (1) to have potent an-
ticonvulsant activity and potential oral anesthetic abil-
ity. Compound 1’s fluorination was originally designed
by us in an effort to avoid the potential formation of
the toxin phenylacylamide (Figure 2).23,24
F igu r e 3. Medicinal chemistry transformations of analogue
1 in the study.
Ta ble 1. Subcutaneous Administration in Mice for Compound
1
Phase I
time (h)
Using traditional medicinal chemistry transforma-
tions, we designed a series of compounds to explore the
SAR of stepwise changes in electronic, conformational,
and lipophilic properties of 1 on general anesthesia
(Figure 3). With this in mind, compound 2 was used to
evaluate the effects of different halogens on the methyl
group on anesthetic activity. Analogues 3 and 9 are
methylene-inserted derivatives of 1 and explore the
steric tolerance of the aromatic and aliphatic-binding
regions. Compounds 4 and 5 represent homologous
transformations introducing charge into the amide
region. Analogue 6 has increased the steric bulk in the
hydroxyl-binding region as compared to compound 1.
Compounds 7 and 8 are ring-closed analogues of the
lead 1 and will allow us to evaluate the effects of phenyl
ring conformation on general anesthetic activity.
dose (mg/kg)
0.5
4.0
30
100
300
30
100
300
30
0/1
3/3
1/1
0/1
5/5
1/1
0/4
4/8
4/4b
0/1
3/3
1/1
0/1
0/1
1/1
0/2
2/4c
2/2a
MES
scMet
rotorod
100
300
Anesthesia. b Loss of righting reflex. c Unable to grasp rotorod.
a
evaluation of compound 1 administered intraperito-
neally (ip) in mice (Table 1) demonstrated complete (4/4
mice) protection at a dose of 100 mg/kg up to 4 h when
challenged with MES. Compound 1 also demonstrated
effectiveness against scMet (5/5 mice protected) for 0.5
h at the same dose. At a 100 mg/kg dose, 50% of the
mice were unable to grasp the rotating rod and exhibited
the loss of the righting reflex upon falling off the rod.
Interestingly enough, anesthesia was observed and
Resu lts
Compound 1 was synthesized (Scheme 1) and 300 mg
sent to the NINDS ADD program. Anticonvulsant

2496 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Choudhury-Mukherjee et al.
Ta ble 2. Oral Anticonvulsant Data in Rats for Analogue 1
Ta ble 3. Effects on MAC Reduction and Blood Pressure in
Rats for Analogues in This Study
Phase II, mg/kga
mean BPa
(mmHg)
MES
ED50
scMET
ED50
rotorod
ED50
MAC (vol %)
compd
T. I.b
compound
( SEM
reductiona ( SEM
log pb
1
9.9
(6.9-13)
9.5
39
100
66
MES 10
ScMET 2.6
MES 6.9
Themisone
127 ( 7
119 ( 12
81 ( 10
111 ( 5
116 ( 3
116 ( 5
121 ( 9
113 ( 4
112 ( 7
107 ( 2
0.0 ( 0
-34 ( 3
-43 ( 3
0.0 ( 0
-6.5 ( 2
-9.1 ( 4
-4.4 ( 3
-4.3 ( 3
-4.4 ( 3
-11 ( 3
0.62
1.3
1.5
1.5
1.4
1.9
3.4
1.1
1.4
1.5
(25-52)
1
2
3
4
5
6
7
8
9
phenytoin
>300
(53-72)
a
b
( ) 95% confidence level. T.I. ) therapeutic index.
Sch em e 2
a
All compounds tested at 60 mg/kg administered by intraperi-
b
toneal injection. Log p calculation using the Crippen’s method
in Chemdraw.
ketone 16 to produce the cyanohydrin, and then the
hydroxyamide was made using the method discussed
above.
Sch em e 3
The anesthetic observation reported in Table 1 by the
NINDS ADD program led us to evaluate compound 1
independently for anesthetic activity. Testing was per-
formed on rats to determine the percent reduction in
the concentration of isoflurane required to prevent the
response to a standardized stimulus. The rats were first
induced with isoflurane, intubated, and ventilated, and
then femoral arterial and venous lines were inserted.
After the rat had been stable for 15 min, the initial
minimum alveolar concentration (MAC) value was
determined. Then 60 mg/kg of drug was sonicated in 3
mL of peanut oil and injected ip. After an additional 30
min, the second MAC value was determined. Finally,
after 1 h the third MAC value was determined. At each
MAC determination, a sample of blood was taken to
determine pH, pCO2, and pO2.
SARs between mean BP and isoflurane MAC reduc-
tion (Table 3) were revealing. Analogue 1 exhibited a
34% reduction in isoflurane MAC with no effects on
blood pressure at 60 mg/kg. An increase in halogen size
(fluorine to chlorine) resulted in improved MAC reduc-
tion (43%) with a large drop in blood pressure at the
same dose for compound 2. This demonstrates that
haliform content is important to anesthetic activity and
blood pressure. A methylene insertion between the
quaternary carbon and the phenyl ring (3 vs 1) did not
improve MAC reduction. Likewise, compound 9, which
possesses a methylene insertion between the quaternary
carbon and the trifluoromethyl group, also did not
demonstrate ability to greatly reduce the MAC. Taken
together, these data suggest that the CF3 and phenyl
ring regions do not tolerate a probe depth of greater
than a methylene group in this region.
reported at a dose of 300 mg/kg in 2/2 animals with
effects up to 4 h. Our laboratory provided another 1000
mg of compound 1 to the NINDS ADD program, which
revealed a MES ED50 of 9.9 mg/kg, scMet ED50 of 39
mg/kg, and TD50 of 100 mg/kg upon oral administration
(Table 2).
With the emergent anesthetic activity of 1, compounds
2-9 were synthesized and evaluated for general anes-
thetic activity. The general synthetic methods are shown
in Schemes 1-3. Final products 1, 2, 3, 9, and themisone
were synthesized by converting the corresponding ke-
tones to the trimethylsilyl ether with trimethyl silyl
cyanide (TMSCN). Subsequent hydrolysis with 15% HCl
generated the cyanohydrin. Conversion of the corre-
sponding cyanohydrin to the hydroxyamide was ac-
complished under acidic conditions by saturating with
HCl gas and allowing the mixtures to stand at room
temperature for 16 h (Scheme 1). Analogue 1 was heated
at 100 °C for 24 h in concentrated HCl to obtain 5, the
acid of the lead compound. Analogues 7 and 8 were
obtained by treating isatin and methyl-isatin with
TMS-CF3 to generate the TMS ether (Scheme 2), and
the TMS ethers were hydrolyzed with acid to obtain the
final products. Analogue 4 was synthesized from the
reduction of compound 11 with LiAlH4.
Compound 4 places a protonated amine in the region
of the amide (1 vs 4). This essentially places a positive
charge in this region. The SAR reveals a decreased MAC
reduction without effects on blood pressure. Compound
5, which contains a negative group (COO-) in the amide
region, also did not demonstrate any statistical increase
in MAC reduction in comparison to analogue 4. These
data suggest that charged groups in this area do not
contribute significantly to activity in comparison to that
of the neutral amide in 1.
Compound 9 was synthesized by reacting dimethyl-
hydrazine with benzaldehyde to give the N′-benzylidene-
N,N-dimethyl-hydrazine 14. Addition of the anhydride
generated the methyl-(3,3,3-trifluoro-1-phenyl-prope-
nyl)-diazene 15. Intermediate 15 was converted to the
3,3,3-trifluoro-1-phenyl-propan-1-one 16 under acidic
conditions (Scheme 3).25 TMSCN was added to the
Compound 6 places steric bulk in the hydroxyl region
and lacks the ability to hydrogen bond in comparison

Propionamide Analogues as Oral General Anesthetics
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2497
to compound 1. Both of these properties appear to
decrease the ability to reduce the MAC and do not
modulate blood pressure.
Compounds 7 and 8 were designed to evaluate phenyl
ring conformation. Both compounds have restricted
phenyl ring rotation. In both cases, the N-methylated
and the NH-restricted analogues do not possess the
ability to reduce the MAC. These compounds hold the
phenyl ring outside of the range of lowest-energy
conformers for lead 1 and have poor anesthetic activity.
This suggests that phenyl ring orientation is important.
A poor correlation (R2 ) 0.4) of mean BP and percent
MAC reduction in Table 3 was also obtained. This is
encouraging and suggests the possibility of developing
compounds that have effects on MAC reduction but are
devoid of effects on BP.
Recent data support that ketamine interacts with
sodium channels in a local anesthetic-like fashion,
including sharing a binding site with commonly used
clinical local anesthetics. Ketamine (Figure 1) blocked
sodium channels in a local anesthetic-like fashion,
exhibiting tonic blockade (concentration for half-maxi-
mal inhibition, IC50 ) 0.8 mM), phasic blockade (IC50
) 2.3 mM), and leftward shift of the steady-state
inactivation.26 Our previous demonstration that phen-
ylhydroxyamides bind to the hydantoin-anesthetic
binding site in the novel voltage-gated sodium channel27
led us to evaluate this mechanism for these similar
compounds. We evaluated the effects of 10 µM and 100
µM of analogue 1 on rNaV 1.3 and rNaV 1.3 coexpressed
with â 3 in xenopus oocytes and in HEK293. The results
of this study demonstrate that analogue 1 does not block
voltage-gated Na+ channels.
Other mechanisms of action thus far include K+
channels and protein kinase C. Compound 1 did not
activate or inhibit rat TASK-1- and TASK-3-leak K+
channels expressed in HEK293 cells at 100 µM. Com-
pound 1 also did not activate protein kinase C at 100
µM.
Preliminary experiments to investigate addictive
potentials were also unrevealing. We found no effects
when the µ-opioid receptor antagonist naloxone was
administered in an attempt to reverse the hemodynamic
depression and MAC reduction following treatment with
analogue 1.
As a method of exploring the mechanism of action,
we pursued a liposome partitioning methodology. It has
been found that xenon, when equilibrated with a
membrane anesthetic model, interacts preferentially
with the amphiphilic regions of the lipid. This is unlike
nonanesthetics which partition deep into the core of the
membrane.28 1-Palmitoyl-2-oleoyl-sn-glycero-3-phospho-
choline (POPC) was chosen as the lipid membrane
environment to evaluate our compounds for lipid par-
titioning. The buffer (pH ) 7.0) was 10 mM K2HPO4‚
3H2O in 20% D2O. The trifluoromethyl functionality
allowed us to utilize 19F NMR for measurements be-
cause the functional group resulted in a sharp singlet
in the spectrum and compounds 1 and 3 were evaluated
for lipid membrane partitioning. Compound 3 was
chosen because it was not found to lower the MAC of
isoflurane at 60 mg/kg in a rat model for general
anesthesia, thus labeled as a nonanesthetic for this
study, whereas 1, which lowered the MAC by 33%,
F igu r e 4. Determination of partition coefficients using 19F
NMR.
represents a potent anesthetic. The observed chemical
shifts were referenced to the compounds in a lipid-free
environment in buffer. Using a simplified two-site
exchange model (eq 1) and a plot of the reciprocal of
frequency changes as a function of the reciprocal of lipid
concentration, we can calculate the partitioning coef-
ficient.
1
1
54.4 × 103
1
m
)
1 +
×
(1)
[
]
∆ν νM - νW
DM/DW
In the above model, mw (molarity of water) was used
as 54.4 × 103 mM because a 1:4 (v/v) mixture of
D2O:H2O was used in the buffer and m is the molarity
of the lipid. The symbols νM and νW represent the
frequencies in pure lipid and water. With a fast ex-
change between the lipid and water layers, the recipro-
cal graph yields a straight line (Figure 4) and the
partition coefficient (DM/DW) is the intercept/slope times
mw. The coefficient was found to be 240 for compound 1
and 1180 for compound 3. Therefore, when equal
amount of 1 and 3 are added to a membrane system,
the concentration of 1 bound to the membrane will be
4.9 times greater than the membrane-bound concentra-
tion of 3. These data are consistent with nonanesthetics
having higher partition coefficients and partitioning into
the core of the membrane. Once more compounds have
been used in the study, we hope to make decisive
correlates between MAC reduction and partitioning in
regards to the mechanism of action.
Several anesthetic agents including propofol enhance
GABAA receptor currents. It was therefore important
to evaluate effects of compound 1 on GABAA receptors
in rat hippocampal neurons. Hippocampal neurons in
culture for 10-14 days were studied with whole-cell
patch-clamp recording technique. Application of 1 mM
of compound 1 evoked GABAA currents at 10 µM (Figure
5).
Discu ssion
Volatile anesthetics are routinely utilized to produce
surgical anesthesia. Although it is rapidly titratable,

2498 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Choudhury-Mukherjee et al.
7.24 ppm (s) in the 1H spectra and 77.0 ppm (t) in the 13C
spectra. IR spectra were recorded on either a Perkin-Elmer
1310 or FT-IR Impact 400D. High-resolution mass spectrom-
etry was performed at the UIUC School of Chemical Science.
Elemental analyses were performed by Atlantic Microlabs.
Concentration in vacuo refers to high vacuum (0.35 mmHg).
Concentration refers to a rotary evaporator with a water
aspirator. Anhydrous THF, diethyl ether, and dichloromethane
were purified by pressure filtration through activated alumina.
Flash chromatography was performed on silica gel (Merck
grade 9385, 230-400 mesh, 60 Å).
Gen er a l P r ep a r a tion of Cya n oh yd r in s fr om Keton es.
The ketone (1.0 equiv) was dissolved in dry CH2Cl2. Trimeth-
ylsilyl cyanide (2.2 equiv) and ZnI2 (1.0 equiv) (or KCN and
18-crown-6, 10 mg each for every 1.0 mmol of ketone) were
added. The mixture was stirred at room temperature for 4 h.
The reaction progress was monitered by TLC, by the dis-
appearance of the carbonyl stretching peak (1770 cm-1), and
F igu r e 5. Compound 1 (1 mM) enhances 10 µM GABAA
currents in rat hippocampal neurons.
volatile anesthetic administration is limited because of
depression of myocardial contractility and peripheral
vasodilation resulting in decreased blood pressure. In
clinical practice, a balanced anesthetic is frequently
obtained by the concurrent administration of a combi-
nation of drugs.
by the appearance of the nitrile stretching peak (2200 cm-1
)
in the IR spectrum. The CH2Cl2 layer was concentrated in
vacuo, and a minimal amount of dry THF was added. The
mixture was cooled to 0 °C, and 15% HCl (5 mL) was added
and then stirred at room temperature for 2 h. The solution
was diluted with H2O and extracted with Et2O (3 × 25 mL),
dried over MgSO4, filtered, and concentrated to yield the
product.
General anesthetics have demonstrated both anticon-
vulsant and proconvulsant activity.29 One possible factor
is an inherent pharmacodynamic variability in the
responsiveness of inhibitory and excitatory target tis-
sues in the central nervous system. This variability in
neuronal responsiveness could also explain the conflict-
ing findings for low versus high doses of fentanyl and
etomidate. Furthermore, biological variation in the
individual patient’s responsiveness to certain anesthetic
drugs could be an additional contributory factor. Dif-
ferent SARs might also explain why some anesthetic
agents possess both proconvulsant and anticonvulsant
properties. Therefore, identification of mechanism(s) will
be useful in further development of compound 1. Along
with the anesthetic effect, compound 1 also demon-
strated potent anticonvulsant activity. Independently,
30 mg/kg of compound 1 provided complete (4/4 animals)
antiseizure protection in rats subjected to MES. As an
anticonvulsant, compound 1’s antiseizure profile (MES
ED50 of 9.9 mg/kg, scMet ED50 of 39 mg/kg, and TD50 of
100 mg/kg) was equally efficacious to phenytoin (a
currently clinically prescribed sodium channel active
anticonvulsant) and exhibited consistently lower neu-
rotoxicity.
2-Hyd r oxy-2-p h en yl-p r op ion itr ile (10) was obtained as
a colorless oil (6.2 g, 100%). IR: (neat) 2220, 3400 cm-1
.
3,3,3-Tr iflu or o-2-h yd r oxy-2-p h en yl-p r op ion itr ile (11)
was obtained as a white solid (8.0 g, 99%). IR: (neat) 2240,
3360 cm-1
.
3-Ch lor o-3,3-d iflu or o-2-h yd r oxy-2-p h en yl-p r op ion i-
tr ile (12) was obtained as a yellow oil (3.3 g, 96%). IR: (neat)
2246, 3383 cm-1
.
2-Ben zyl-3,3,3-Tr iflu or o-2-h yd r oxy-p r op ion itr ile (13)
was obtained as a light yellow solid (1.3 g, 94%). IR: (neat)
2244, 3384 cm-1
.
4,4,4-Tr iflu or o-2-h yd r oxy-2-p h en yl-bu tyr on itr ile (17)
was obtained as a brown oil (1.8 g, 97%). IR: (neat) 2248, 3403
cm-1
.
Gen er a l P r ep a r a tion of r-Hyd r oxya m id es fr om Cy-
a n oh yd r in s. The cyanohydrin was dissolved in 1,4-dioxane
(2 mL) and cooled to 0 °C. Previously cooled concentrated HCl
(0.2 mL for every 1 mmol of cyanohydrin) was added. HCl gas
was then passed through the reaction mixture for 45 min at
0 °C. The mixture was then allowed to stand, without stirring,
at room temperature for 16 h. The mixture was extracted with
EtOAc (3 × 25 mL), dried over MgSO4, filtered, and concen-
trated to yield the crude R-hydroxyamide. Purification was
performed on a flash column (1:1 hexanes:EtOAc), collecting
all fractions with a component of Rf ) 0.28 to yield the pure
R-hydroxyamide.
Con clu sion
2-Hyd r oxy-2-p h en yl-p r op ion a m id e (Th em ison e) was
obtained as a white solid (288 mg, 30%): mp 97-99 °C. 1H
NMR: δ 2.15 (s, 3H), 6.61 (d, J ) 7.7 Hz, 2H), 7.10-7.71 (m,
5H). 13C NMR: δ 29.8, 72.0, 129.9, 128.4, 128.5, 141.3, 173.7.
IR (KBr): 1733, 3193, 3371 cm-1. APCI MS m/z: 148.1, loss of
H2O, (M + H+).
We have demonstrated the MAC-reducing effect of a
novel class of phenylamide derivatives and are encour-
aged that compound 1 was hemodynamically well toler-
ated at therapeutically relevant doses separate from
toxicity. This study confirms that compound 1 does
indeed possess potent general anesthetic activity and
appears devoid of significant side effects (i.e., altering
blood pressure or heart rate or causing respiratory
depression).
3,3,3-Tr iflu or o-2-h yd r oxy-2-p h en yl-p r op ion a m id e (1)30
1
was obtained as a white solid (8.6 g, 99%): mp 83-85 °C. H
NMR: δ 4.84 (s, 1H), 6.25 (d, J ) 26.4 Hz, 2H), 7.67-7.42 (m,
5H). 13C NMR: δ 121.7, 125.5, 126.2, 128.9, 129.6, 129.8, 134.0,
169.5 134.0. IR (KBr): 1697, 3360 cm-1. APCI MS m/z: 220.0
(M + H+). HRMS (EI): calcd for C9H8F3NO2, 219.0507; found,
219.0507. Anal. Calcd for C9H8F3NO2: C, 49.32; H, 3.68; N,
6.39. Found: C, 49.62; H, 3.63; N, 6.45.
Exp er im en ta l Section
Ch em istr y. All reactions requiring anhydrous conditions
were performed in flame-dried glassware under an argon or
nitrogen atmospherere. Melting points were determined with
an Electrothermal Mel-Temp melting point apparatus and are
uncorrected. 1H and 13C NMR spectra were measured on a
General Electric 300 MHz instrument, unless specified oth-
erwise. Chemical shifts are reported in ppm relative to
resonances of the solvent, CDCl3 (unless specified otherwise):
3-Ch lor o-3,3-d iflu or o-2-h yd r oxy-2-p h en yl-p r op ion a -
m id e (2) was obtained as a white solid (1.8 g, 50%): mp 79-
81 °C. 1H NMR: (CD3OD) δ 7.76-7.31 (m, 5H). 13C NMR:
(CD3OD) δ 126.7, 127.8, 129.0, 130.0, 130.7, 134.7, 136.4, 173.0.
IR (KBr): 1700, 3224, 3340, 3510 cm-1. APCI MS m/z: 236.0
(M + H+). HRMS (EI) calcd for C9H8ClF2NO2, 235.0212; found,
235.0214. Anal. Calcd for C9H8ClF2NO2: C, 45.88; H, 3.42; N,
5.94. Found: C, 45.88; H, 3.44; N, 6.01.

Propionamide Analogues as Oral General Anesthetics
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12 2499
2-Ben zyl-3,3,3-tr iflu or o-2-h yd r oxy-p r op ion a m id e (3)
was obtained as a white solid (1.1 g, 78%): mp 114-116 °C.
1H NMR: (CD3OD) δ 2.94 (d, J ) 13.5 Hz, 1H), 3.36 (d, J )
13.8 Hz, 1H), 7.22-7.16 (m, 5H). 13C NMR: (CD3OD) δ 38.4,
78.8, 110.2, 123.5, 127.3, 127.6, 128.5, 131.2, 134.5, 171.4. IR
(KBr): 1700, 3210, 3385, 3503 cm-1. ESI MS m/z: 232.2 (M -
H-). HRMS (EI): calcd for C10H10F3NO2, 233.0664; found,
233.0668. Anal. Calcd for C10H10F3NO2: C, 51.51; H, 4.32; N,
6.01. Found: C, 51.27; H, 4.36; N, 5.99.
solution of t-BuOK in dry THF (30 mL) was added until the
reaction began to reflux. The mixture was then brought to
ambient temperature and allowed to stir for 2 h. The mixture
was extracted with hexanes (3 × 40 mL), dried over MgSO4,
filtered, and concentrated. The crude product was dissolved
in dry THF (5 mL), cooled to 0 °C, and 15% HCl (6 mL) was
added and allowed to stir for 15 min. The mixture was
extracted with hexanes (3 × 40 mL), dried over MgSO4,
filtered, and concentrated to yield the crude product. Purifica-
tion was performed on a flash column (10:1 CH2Cl2:acetone),
collecting all fractions containing a component of Rf ) 0.81 to
yield the pure product.
4,4,4-Tr iflu or o-2-h yd r oxy-2-p h en yl-bu tyr a m id e (9) was
1
obtained as white solid (1.6 g, 82%): mp 75-76 °C. H NMR:
δ 2.70 (m, 1H), 3.30 (m, 1H), 4.02 (bs, 1H), 5.62 (s, 1H), 6.77
(s, 1H), 7.48-7.33 (m, 5H). 13C NMR: δ 41.8, 109.3, 123.6,
124.7, 127.2, 128.4, 128.6, 140.8, 174.9. IR (KBr): 1675, 3426
cm-1. ESI MS m/z: 232.3 (M - H-). HRMS (EI): calcd for
3-Hyd r oxy-3-tr iflu or om eth yl-1,3-d ih yd r o-in d ol-2-on e
(7) was obtained as
a white solid (4.4 g, 75%): mp
194-196 °C. 1H NMR: δ 4.81 (s, 1H), 6.7-7.5 (m, 4H). 13C
NMR: δ 110.6, 122.0, 123.0, 125.1, 125.8, 126.0, 131.5, 143.1,
173.7. IR (KBr): 1717, 3421 cm-1. APCI MS m/z: 218.0 (M +
H+). HRMS (EI): calcd for C9H6F3NO2, 217.0351; found,
217.0352.
C
10H10F3NO2, 233.0664; found, 233.0665. Anal. Calcd for
C10H10F3NO2: C, 51.51; H, 4.32; N, 6.01. Found: C, 51.62; H,
4.27; N, 6.03.
P r ep a r a tion of 3-Am in o-1,1,1-tr iflu or o-2-p h en yl-p r o-
p a n -2-ol (4).31 3,3,3-Trifluoro-2-hydroxy-2-phenyl-propionitrile
(11) (1.0 g, 5.0 mmol) was dissolved in dry Et2O (2 mL) and
added to cold (0 °C) LiAlH4 (0.2 g, 5.3 mmol) dissolved in dry
Et2O (4 mL). The reaction mixture was stirred at room
temperature for 2 h, then cooled to 0 °C. After allowing the
reaction mixture to warm to room temperature, H2O (0.8 mL)
and 15% NaOH (0.2 mL) were added dropwise. The precipitate
was filtered, washed with Et2O, and concentrated. Purification
was performed on a flash column (3:2 hexanes:EtOAc), col-
lecting all fractions with a component of Rf ) 0.14. The product
was recrystallized from 1:1 hexanes:EtOAc to yield a white
3-Hyd r oxy-1-m eth yl-3-tr iflu or om eth yl-1,3-d ih yd r o-in -
d ol-2-on e (8) was obtained as a yellow solid (2.2 g, 35%): mp
168-170 °C. 1H NMR: δ 3.18 (s, 3H), 4.75 (s, 1H), 7.0-7.5
(m, 5H). 13C NMR: δ 25.8, 109.4, 123.5, 123.6, 124.5, 125.7,
125.8, 131.8, 144.8, 171.8. IR (KBr): 1717, 3302 cm-1. APCI
MS m/z: 232.0 (M + H+). HRMS (EI): calcd for C10H8F3NO2,
231.0507; found, 231.0509. Anal. Calcd for C10H8F3NO2: C,
51.96; H, 3.49; N, 6.06. Found: C, 52.22; H, 3.45; N, 6.01.
P r ep a r a tion of N′-Ben zylid en e-N,N-d im eth yl-h yd r a -
zin e (14). Benzaldehyde (0.5 g, 4.7 mmol) and ethanol (24 mL)
were cooled to 10 °C, and a solution containing N,N-dimeth-
ylhydrazine (0.54 mL, 7.1 mmol) and ethanol (5 mL) was added
dropwise. The resulting mixture was allowed to warm to
ambient temperature, followed by stirring for 30 min, and then
heated to reflux for 24 h. After cooling, the reaction mixture
was concentrated in vacuo and the resulting mixture diluted
with H2O and extracted with Et2O (3 × 20 mL). The organic
layer was washed with brine, dried over Na2SO4, filtered, and
1
solid (600 mg, 58%): mp 57-59 °C. H NMR: δ 3.04 (d, J )
13.5 Hz, 1H), 3.52 (d, J ) 13.2 Hz, 1H), 7.60-7.38 (m, 5H).
13C NMR: δ 46.0, 125.0, 126.7, 128.2, 128.8, 129.0, 137.9. IR
(KBr): 2973, 3349 cm-1. APCI MS m/z: 206.1 (M + H+). HRMS
(EI): calcd for C9H10F3NO, 206.0793; found, 206.0789. Anal.
Calcd for C9H10F3NO: C, 52.68; H, 4.91; N, 6.83. Found: C,
52.87; H, 5.02; N, 6.78.
1
concentrated to yield a colorless oil (636 mg, 91%). H NMR:
P r ep a r a t ion of 3,3,3-Tr iflu or o-2-h yd r oxy-2-p h en yl-
p r op ion ic Acid (5). A solution of 1 (1.0 g, 4.6 mmol) was
dissolved in 1,4-dioxane (1.5 mL). Concentrated HCl (2.5 mL)
was added to the reaction mixture dropwise at 0 °C. The
mixture was heated at 100 °C for 24 h. After cooling, the
solution was washed with H2O (4 × 20 mL) and concentrated.
Purification was performed on a flash column (1:1 hexanes:
EtOAc), collecting all fractions with a component of Rf ) 0.20
δ 3.02 (s, 6H), 7.31-7.45 (m, 5H), 7.70 (s, 1H). 13C NMR: δ
43.4, 126.2, 127.9, 129.1, 133.2, 137.6. The product was used
without further purification.
P r ep a r a tion of Meth yl-(3,3,3-tr iflu or o-1-p h en yl-p r o-
p en yl)-d ia zen e (15). To a solution of 16 (2.0 g, 13.5 mmol)
in pyridine (40 mL) at 0 °C was added trifluoroacetic anhydride
(18 mL, 130 mmol) dropwise with stirring. After stirring for 5
h at room temperature, the solution was concentrated in vacuo,
and CH2Cl2 was added to the residue. The mixture was washed
with 0.1 N HCl (100 mL), H2O (100 mL), and saturated Na2-
CO3 (100 mL). The organic layer was dried over MgSO4,
filtered, and concentrated to give an oil (2.1 g, 76%). The
product was used without further purification. All spectral
data matched the one from the literature.25
1
to yield a white solid (700 mg, 70%): mp 96-97 °C. H NMR:
δ 7.69-7.32 (m, 5H). 13C NMR: δ 170.2, 134.9, 129.7, 129.3,
128.3, 126.8, 126.0, 122.3, 109.9. IR (KBr): 1735, 3403 cm-1
.
EI MS m/z: 220.0. HRMS (EI): calcd for C9H7F3O3, 220.0344;
found, 220.0343. Anal. Calcd for C9H7F3O3: C, 49.10; H, 3.20.
Found: C, 48.99; H, 3.21.
P r ep a r a t ion of 2-Ben zyloxy-3,3,3-t r iflu or o-2-p h en yl-
p r op ion a m id e (6).32 Compound 1 (0.63 g, 2.9 mmol) was
dissolved in dry CH2Cl2 (14 mL), and 5% NaOH (7 mL) was
added. Benzyl bromide (0.5 g, 2.9 mmol) was added, and the
mixture was allowed to stir for 10 min. Bu4NBr (0.1 g, 0.3
mmol) was added to the reaction mixture and stirred for 16 h
at room temperature. The organic layer was washed with H2O
(3 × 10 mL), dried over Na2SO4, filtered, and concentrated.
Purification was performed on a flash column (3:1 hexanes:
EtOAc), collecting all fractions with a component of Rf ) 0.35.
The product was recrystallized from hot toluene to yield a
white solid (605 mg, 68%): mp 70-72 °C. 1H NMR: δ 4.61
(m, 2H), 6.68 (d, 2H), 7.64-7.34 (m, 10H). 13C NMR: δ 69.4,
109.3, 125.7, 127.7, 128.5, 128.7, 128.9, 129.0, 129.7, 132.4,
136.7, 169.4. IR (KBr): 3227, 1700 cm-1. ESI MS m/z: 308.5
(M - H-). HRMS (EI): calcd for C16H14F3NO2, 309.0977; found,
309.0979. Anal. Calcd for C16H14F3NO2: C, 62.13; H, 4.56; N,
4.53. Found: C, 62.20; H, 4.63; N, 4.59.
P r ep a r a tion of 3,3,3-Tr iflu or o-1-p h en yl-p r op a n -1-on e
(16). A solution of 15 (2.1 g, 9.8 mmol) in CH3CN (20 mL) and
6 N HCl (20 mL) was allowed to stir for 24 h at room
temperature. The mixture was concentrated in vacuo, ex-
tracted with CH2Cl2 (4 × 20 mL), dried over Na2SO4, filtered,
and concentrated to yield an oil (450 mg, 13%). 1H NMR: δ
3.79 (q, J ) 9.9 Hz, 2H), 8.05-7.20 (m, 5H). 13C NMR: δ 42.6
2
(q, J CF ) 28.2 Hz), 109.9, 128.8, 129.4, 134.7, 136.3, 190.2.
IR (neat): 1700, 3200 cm-1
.
Biology
Ver tebr a te An im a ls. The Department of Comparative
Anatomy operates a vivarium that is fully accredited by the
American Association for Accreditation of Laboratory Animal
Care. Standard experimental protocols were used to determine
anesthetic activity and were approved by the Animal Care and
Use Committee at the University of Virginia.
Meth od s for Deter m in in g MAC. This model was used as
a screening test using animals receiving a 60 mg/kg dose
administered ip. In addition, this method allows for a more
detailed examination of the anesthetic-sparing properties of
selected compounds over a greater dose range. Male Sprague-
Dawley rats were placed in a clear plastic cone and anesthe-
Gen er a l P r oced u r e for th e P r ep a r a tion of Tr iflu or i-
n a ted Isa tin Der iva tives. Anhydrous KF (510 mg, 5.4 mmol)
and a solution of isatin or methylisatin (27.2 mmol) in dry THF
(100 mL) were added dropwise via syringe, followed by
trimethyl(trifuoromethyl)silyl (5.8 g, 40.8 mmol). A saturated

2500 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 12
Choudhury-Mukherjee et al.
tized with 5% isoflurane (Ohmeda; Liberty Corner, NJ ) and
oxygen for 3-5 min. The inspired isoflurane concentration was
reduced to 2%, and the animal was allowed to breathe
spontaneously until cannulation of a femoral artery and vein
with a 24-gauge polyethylene catheter (J ohnson and J ohnson
Medical Inc., Arlington, TX) had been accomplished. The
trachea was then intubated with a 16-gauge polyethylene
catheter (J ohnson and J ohnson Medical Inc., Arlington, TX).
The isoflurane concentration was decreased further to 1.5%
and ventilation controlled with a Harvard animal respirator
using measurement of arterial blood gases (IRMA series 2000
Blood Analysis System, Diametric Medical Inc., St. Paul, MN)
to maintain normal pO2, pCO2, and pH. Alveolar isoflurane
concentrations and end-tidal CO2 measurements were obtained
using a Datex Engstrom Capnomac gas monitor (Helsinki,
Finland). Additional confirmation of volatile anesthetic con-
centrations was obtained using gas chromatography. Heart
rate and systolic and diastolic blood pressures were monitored
and recorded using an ADInstruments MacLab (Mountain
View, CA) data recording system. Temperature was measured
using a FHC temperature controller (FHC, Bowdoinham, ME)
and maintained at normothermia using a heating blanket and
warming lights. Under control conditions, the MAC was
established according to the methods described by Eger and
colleagues using a long hemostat (8-in. Rochester Dean
hemostatic forceps) clamped to the first ratchet lock on the
tail for 1 min.33 The tail was stimulated proximal to a previous
test site. Gross movement of the head, extremities, body, or
all three were taken as a positive test, whereas grimacing,
swallowing, chewing, or tail flick were considered negative.
The isoflurane concentration was reduced in decrements of
0.1% until the negative response became positive, allowing 12-
15 min equilibration after changes in concentration. The MAC
was considered to be the concentration midway between the
highest concentration that permitted movement in response
to the stimulus and the lowest concentration that prevented
movement.
concentration of GABA was selected for several reasons. First,
it is on the rising phase of the GABA concentration-response
curve, allowing accurate assessment of enhancement without
saturating maximum current. Second, with 10 µM, GABA
desensitization was minimal and the GABAR current rundown
was slow, thus reducing trial-to-trial variability of responses.
The magnitude of the enhancement or inhibition of the
GABAA receptor current by compound 1 was measured by
dividing the peak amplitude of the GABAA receptor current
elicited in the presence of a given concentration of the drug
and GABA by the peak amplitude of control current elicited
by GABA alone and multiplying the fraction by 100 to express
it as percent control (eq 2).
Imax
I )
(2)
EC50 - logdrug)(Hill‚slope)
1 + 10(log
Thus the control response was 100%. Peak GABAA receptor
currents at various concentrations of compound 1 were fitted
to a sigmoidal function using a four-parameter logistic equa-
tion with a variable slope. Equation 2 was used to fit the
concentration-response relationship, where I is the GABAR
current at a given GABA concentration and I(max) was the
maximal GABAR current. Maximal current and concentra-
tion-response curves were obtained after pooling data from
all neurons tested for GABA. Convergence was reached when
two consecutive iterations changed the sum of squares by less
than 0.01%. The curve fit was performed on an IBM PC
compatible personal computer using a prism program (Graph
Pad Software inc., San Diego, CA). All data were presented
as mean ( standard error of the mean.
Ack n ow led gm en t. M.L.B. would like to thank J .
Randall Moorman, M.D., Paul Lenkowski, Manoj Patel,
Ph.D., J ulianne Sando, Ph.D., Carl Lynch, M.D., Ph.D.,
Doug Bayliss, Ph.D., and J ames Stables for contribu-
tions to this study and the J effress Trust Fund and the
UVA department of chemistry for financial support.
Compounds with limited aqueous solubility were adminis-
tered by intraperitoneal injection after being sonicated in
peanut oil (3 mL). We have previously shown the lack of effect
of the vehicle (peanut oil) on MAC determinations.34 After
determination of the baseline MAC, the compounds were
administered by intraperitoneal injection. The order of ad-
ministration of the various doses was performed in an un-
blinded, random manner. A single investigator performed all
the MAC determinations to reduce inter-observer variability.
Four animals were typically studied at each dose. An isoflu-
rane concentration was chosen at the movement that did not
occur in the last negative response before the positive test. At
this isoflurane concentration, 30 min after the administration
of the test compound, the MAC was again determined with
the concentration of isoflurane reduced and the response to
the tail clamp was checked every 12-15 min thereafter until
a positive response was achieved. After recording the experi-
mental MAC, an additional hour was allowed to elapse before
the MAC was again determined. Assessment of differences in
anesthetic activity and effects on heart rate and blood pressure
was performed by multifactor analysis of variance (ANOVA)
models fit using restricted maximum likelihood techniques.
All models included an adjustment for any effects associated
with the experiment. A natural logarithmic transformation of
anesthetic activity and effects on heart rate and blood pressure
was employed. This allowed for the use of the anti-logarithm
of differences to compare the ratio of two quantities (inter-
preted as fold change) and aided in meeting the assumptions
of the linear model (constant variance across categories and
normally distributed error terms).
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